The growth of cancerous prostate cells requires stimulation of the androgen receptor (AR) by androgens, the most potent of which is dihydrotestosterone (DHT). Advanced prostate cancer usually initially regresses with gonadal testosterone deprivation therapy (i.e., medical or surgical castration), but it almost always eventually progresses as castration-resistant prostate cancer (CRPC). The CRPC phenotype is driven by a gain-of-function in the androgen receptor (AR) that is usually accompanied by intratumoral DHT concentrations of about 1 nM, which is sufficient to drive expression of AR-induced genes, including the TMPRSS2-ETS fusion oncogene. Sharifi, N., Mol Endocrinol 27, 708-714 (2013). The requirement for intratumoral androgen synthesis in driving CRPC progression is most clearly demonstrated by the survival benefit conferred by abiraterone acetate, a drug which blocks androgen synthesis by inhibiting 17α-hydroxylase/17,20-lyase (CYP17A1), and enzalutamide, a potent AR antagonist that blocks DHT access to the AR ligand-binding domain. de Bono et al., N Engl J Med 364, 1995-2005 (2011); Scher et al., N Engl J Med. 367, 1187-97 (2012).
Intratumoral synthesis of DHT from precursors that are secreted from the adrenal gland occurs through a pathway that circumvents testosterone. Chang et al., Proc Natl Acad Sci USA 108, 13728-13733 (2011). This synthesis requires three enzymes: 3β-hydroxysteroid dehydrogenase (3βHSD; encoded by HSD3B), steroid-5α-reductase (SRD5A) and 17β-hydroxysteroid dehydrogenase (17βHSD) isoenzymes (see FIG. 1A). Nonetheless, increased DHT synthesis in CRPC has not yet been ascribed to any mutations in genes encoding components of the steroidogenic machinery. 3βHSD oxidizes 3β-hydroxyl to 3-keto and isomerizes Δ5 to Δ4 (see FIG. 1A), reactions that together make this step practically irreversible by an enzyme that is required for all possible pathways that lead to the synthesis of DHT. Evaul et al., Endocrinology 151, 3514-3520 (2010). HSD3B1 encodes for the peripherally expressed isoenzyme (3βHSD1) and has a germline single nucleotide polymorphism (SNP) at position 1245 of HSD3B1, converting A→C, which exchanges an asparagine (N) for a threonine (T) at 3βHSD1 amino acid position 367.
The past decade has brought to the fore the development of molecularly targeted therapies that are matched to specific disease-driving enzyme mutations present in a given patient. These advances come mainly in the form of tyrosine kinase inhibitors that target gain-of-function mutations in these signaling enzymes. These include the examples of EGF receptor inhibitors matched with tumors harboring mutant EGF receptor in non-small cell lung cancer and BRAF inhibitors for melanomas that are driven by BRAF mutations Chapman et al. N Engl J Med 364, 2507-2516 (2011); Kobayashi et al., N Engl J Med 352, 786-792 (2005). In contrast, no examples of drug targeting based on enzyme mutations exist in the standard of care for metastatic CRPC.